Multiple myeloma in the very elderly patient: challenges and solutions

Figures & data

Figure 1 The challenges of diagnosis and treating the very elderly patient with multiple myeloma.

Abbreviation: VTE, thromboembolism.

Figure 2 Clinical features of myeloma and other diagnoses which may mimic myeloma.

Notes: The incidences of calcium ≥2.75 mmol/L (11 mg/dL), hemoglobin #100 g/L, creatinine ≥177 μmol/L (2 mg/dL), and bone pain at initial diagnosis of myeloma are shown.
Abbreviations: BPH, benign prostatic hypertrophy; CKD, chronic kidney disease; NSAIDs, nonsteroidal anti-inflammatory drugs; eGFR, estimated glomerular filtration rate.

Table 1 Investigations required in very elderly patients with possible plasma cell myeloma

To make the diagnosis
First-line investigations	FBC, U&E, creatinine, calcium, protein electrophoresis, urinary electrophoresis, SFLC ratioa	This should be performed in all patients suspected of having myeloma
To exclude mimics	PTH, blood film, hematinics, fasting glucose	As appropriate to exclude other causes for symptoms and abnormal blood results
Radiology	Skeletal survey MRI spine and pelvis in patients with back pain	All patients, but in the very frail may just target areas of pain
To confirm diagnosis
Bone marrow	Aspiration and trephine	All patients, but consider omitting trephine in frail patients, particularly if combination chemotherapy is inappropriate
Bone marrow	Flow cytometry	Assessment of clonality
To assess disease status
Blood	β2-microglobulin, albumin, LDH	To assess tumor burden and prognosis
Bone marrow	FISH panel	To assess prognosis

Note:

a SFLC should be done if light chain myeloma or nonsecretory myeloma is suspected.

Abbreviations: FBC, full blood count; U&E, urea and electrolytes; SFLC, serum free light chains; PTH, parathyroid hormone; LDH, lactate dehydrogenase; FISH, fluorescence in situ hybridization; MRI, magnetic resonance imaging.

Table 2 Diagnosis of symptomatic myeloma

Clonal population of plasma cells >10%, or biopsy proven plasmacytoma plus one or more of
Evidence of end-organ damage that can be attributed to the plasma cell disorder
Hypercalcemia: calcium >0.25 mmol/L above normal range or >2.75 mmol/L
Renal impairment: creatinine clearance <40 mL/min or creatinine >177 μmol/L
Anemia: hemoglobin >20 g/L below lower limit of normal or <100 g/L
Bony lesions: one or more osteolytic lesions on plain XR/CT/PET-CT
Myeloma defining events in the absence of end-organ damage
Clonal plasma cell population >60%
Ratio of involved: uninvolved SFLC >100 with involved SFLC >100 mg/L
>1 focal lesion of >5 mm in size on MRI

Note: Data from Rajkumar et al.⁶²

Abbreviations: PET-CT, positron emission tomography-computed tomography; SFLC, serum free light chains; MRI, magnetic resonance imaging.

Table 3 A summary of the results of large randomized controlled trial treatment in transplant-ineligible patients with myeloma

Source	Regimens tested	Eligibility	Age (range)	Comorbidities	ORR	OS	PFS	Toxicity
San Miguel et al^Citation38,Citation60	Nine 6-weekly cycles of VMP (n=344) vs MP alone (n=338)	≥65 years or <65 years and ineligible for ASCT	Median 71 years (48–91) Age ≥75 years 30%	5.5% CrCl <30 mL/min 33% history of cardiac condition	PR or better: 71% VMP vs 35% MP CR: 30% VMP vs 4% MP (P<0.001)	Median OS: VMP 56.4 vs MP 43.1 months 5 year OS: VMP 46.0% vs MP 34.4% (P<0.001)	Median TTP: VMP 20.7 months vs MP 15.0 months (HR, 0.54, P<0.001)	Incidence SPM was similar and consistent with background rates
Mateos et al^Citation61	Six cycles of VMP (n=130) vs six cycles of VTP (n=130) as induction, responders: Maintenance VP (n=87) vs VT (n=91)	≥65 years ECOG 0–2	Median 73 years (68–77) Age ≥75 years 34%	Not discussed	105 (81%) in VTP vs 104 (80%) in VMP: PR or better (P=0.9) 36 (28%) in VTP and 26 (20%) VMP: CR (P=0.2)	3-year OS: VMP 74% vs VTP 65% (P=0.3)	Median PFS: VMP 34 months vs VTP 25 months (P=0.1)	VTP: serious AEs (31% vs 15%, P=0.01) and discontinuations (17% vs 12%, P=0.03) vs VMP
Fayers et al^Citation42	Meta-analysis of MPT trials vs MP: (n=1,685 across trials) Thalidomide: 100–400 mg od	>65 years in 3 trials, >55 years in 1 trial, >75 years in 1 trial, 65–75 years in 1 trial	Median ages: 72.5, 72.6, 69.4, 78.5, 74.4, 70.6 years, respectively		1-year ORR (PR or better) 59% MPT vs 37% MP (P=0.0001)	Median OS: MP 32.7 months vs MPT 39.3 months (P=0.004)	Median PFS: MP 14.9 months vs MPT 20.3 months (P<0.0001) No PFS advantage if presenting creatinine >176 (HR, 0.87, P=0.6)	Not detailed
Morgan et al^Citation41	CTDa (n=426) vs MP (n=423)	Nonintensive arm of Myeloma IX trial >18 years, unfit for ASCT	Median 73 years (57–89)	Not discussed, although clear data that those over 80 years have significantly worse OS	ORR: CTDa 63.8% vs MP 32.6% (P<0.0001) CR: CTDa 13.1% vs MP 2.4% VGPR: CTDa 16.9% vs MP 1.7%	Median OS: MP 30.6 months vs CTDa 33.2 months (HR, 0.89, P=0.24)	Median PFS: MP 12.4 months vs CTDa 13.0 months (HR, 0.82, P=0.01)	CTDa associated with higher rates of thromboembolism, constipation, infection, and PN vs MP
Palumbo et al^Citation40	MPR-R (nine 4-weekly cycles of MPR, followed by lenalidomide maintenance to PD) (n=152) vs MPR (n=153) vs MP (n=154)	≥65 years or <65 years and ineligible for ASCT	Median 71 years (65–91) Age ≥75 years 24%	Not discussed	ORR: MPR-R (77%) vs MPR (68%) vs MP 50% (P<0.001 and P=0.002, respectively, for comparison with MP)	3-year OS: MPR-R 70% vs MPR 62% vs MP 66% (HR MPR-R vs MPR: 0.79, P=0.25. HR MPR-R vs MP: 0.95, P=0.81)	Median PFS: MPR-R 31 months vs MPR 14 months (HR, 0.49, P<0.001) vs MP 13 months (HR, 0.40, P<0.001). PFS benefit with MPR-R in 65–75 years of age but not >75 years	Most AEs hematologic; Grade 4 neutropenia: MPR-R 35% vs MPR 32% vs MP 8%. 3 year rate SPM: MPR-R 7% vs MPR 7% vs MP 3%
Benboubker et al^Citation37	cLD to PD (n=535) vs LD18 for 72 weeks (18 cycles; n=541) vs MPT 72 weeks (n=547)	≥65 years or <65 years and ineligible for ASCT	Median 73 years (44–91) Age ≥75 years 35%	9% CrCl <30 mL/min	75% cLD vs 73% LD18 vs 62% MPT (P<0.001: both comparisons with MPT)	4 year OS: 59% cLD vs 56% LD18 vs 51% MPT (HR cLD vs MPT, 0.78; P=0.02. cLD vs LD18, HR, 0.90, P=0.31)	Median PFS: cLD 25.5 months vs LD18 20.7 months vs MPT 21.2 months (HR, 0.72 cLD vs MPT and 0.70 cLD vs LD18, P<0.001 for both comparisons)	Grade 3–4 AEs cLD 70% vs MPT 78%. Compared with MPT, cLD associated with fewer hematologic and neurotoxicity, increased infections, and fewer SPMs
Magarotto et al^Citation49	Rd and lenalidomide–prednisone plus melphalan (MPR) or CPR (n=222), MPR (n=218) or CPR (n=222)	≥65 years	Rd 37%, MPR 39%, CPR 36% ≥75 years	Not discussed	Not discussed	Median OS in ≥75 years: Rd NR vs MPR 37 months vs CPR 43 months (Rd vs MPR P=0.04; Rd vs CPR P=0.430; MPR vs CPR P=0.323)	Median PFS in ≥75 years: Rd 22 months vs MPR 18 months vs CPR 21 months in CPR (Rd vs MPR P=0.572, Rd vs CPR P=0.699, MPR vs CPR P=0.914)	≥1 hematologic Grade 3–4 AE in ≥75 years subgroup: Rd 29% vs MPR 70% vs CPR 33% (MPR vs Rd/CPR P<0.0001). No difference in extrahaematologic AEs
Palumbo et al^Citation39	VMPT plus VT maintenance (VMPT-VT) (n=254) vs VMP (n=257)	≥65 years or <65 years and ineligible for ASCT	Median 71 years Age ≥75 years 27%	Not discussed	CR: 38% VMPT-VT vs 24% VMP	5 year OS: VMP 51% vs VMPT-VT 61% (HR, 0.70; P=0.01)	3 year PFS: VMP 41% vs VMPT-VT 56% median PFS: VMP 24.8 months vs VMPT-VT 35.3 months (HR, 0.58; P=0.001)	Grade 3–4 AE in VMPT-VT: neutropenia (38%), thrombocytopenia (22%), PN (11%), and cardiac events (11%). All except thrombocytopenia, were significantly more frequent in VMPT-VT
Niesvizky et al^Citation45	Eight 21-day cycles VD (n=168) vs VTD (n=167) vs VMP. All arms received V-maintenance	≥65 years or <65 years and ineligible for ASCT	Median 73 years (48–91) Age ≥75 years 42%	48% comorbidities, 19% Charlson comorbidity index ≥2), including DM 21%, renal disease 15%, and chronic pulmonary disease 8%	ORR: VD 73% vs VTD 80% vs VMP 70% CR: VD 3% vs VTD 4% vs VMP 4%	Median OS: VD 49.8 months vs VTD 51.5 months vs VMP 53.1 months (global P=0.79)	Median PFS: VD 14.7 months vs VTD 15.4 months vs VMP 17.3 months (global P=0.46)	PN: VD 50% vs VTD 60% vs VMP Grade ≥2 PN: 35% VD vs VTD 47% vs VMP 35%. Grade ≥3 infection: VD 21%, VTD 16% vs VMP 18%. Grade ≥3 sepsis: VD 3% vs VTD 3% vs VMP 2%

Abbreviations: AEs, adverse events; ASCT, autologous stem cell transplantation; cLD, continuous lenalidomide–dexamethasone; CTDa, attenuated cyclophosphamide, thalidomide, dexamethasone; CPR, cyclophosphamide; CR, complete response; CrCl, creatinine clearance; DM, Diabetes Mellitus; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; MP, velcade, melphalan; MPT, melphalan, prednisolone, thalidomide; MPR ± R, melphalan, prednisolone, revlimid ± revlimid maintenance; NR, not reached; od, once daily; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PN, peripheral neuropathy; PR, partial response; Rd, lenalidomide–dexamethasone; SPM, secondary primary malignancy; TTP, time to treatment failure; VD, velcade, dexamethasone; VGPR, very good partial response; VMP ± T ± VT, velcade, melphalan, prednisolone ± thalidomide ± velcade–thalidomide maintenance; VTP, velcade, thalidomide, prednisolone; VMPT, velcade, melphalan, prednisolone, thalidomide; VTD, velcade, thalidomide, dexamethasone.

Table 4 Choice of therapeutic agent in patients with comorbidity

Comorbid condition	Advice on therapeutic agent
Renal impairment	Prefer bortezomib-based regimes Need to reduce dose if use lenalidomide
Polyneuropathy	Avoid or reduce dose if use bortezomib
Cardiac arrhythmia/dysfunction	Caution with thalidomide and high-dose steroids
Diabetes	Caution with high-dose steroids
Psychiatric/behavioral problems	Caution with high-dose steroids
Bone marrow insufficiency	Caution with cytoreductive drugs Consider single-agent dexamethasone
Poor immune function	Caution with cytoreductive drugs
Poor cognitive function or compliance	Consider subcutaneous and/or hospital-delivered regimes

RajkumarSVDimopoulosMAPalumboAIMWG updated criteria for the diagnosis of multiple myelomaThe Lancet Oncology20141512e538e54825439696

 PubMed Web of Science ®Google Scholar

San MiguelJFSchlagRKhuagevaNKBortezomib plus melphalan and prednisone for initial treatment of multiple myelomaN Engl J Med200828; 3599906917

 Web of Science ®Google Scholar

San MiguelJFSchlagRKhuagevaNKPersistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myelomaJ Clin Oncol201331444845523233713

 PubMed Web of Science ®Google Scholar

MateosMVOriolAMartínez-LópezJBortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myelomLancet Oncol2010111093494120739218

 PubMed Web of Science ®Google Scholar

FayersPMPalumboAHulinCThalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trialsBlood201111851239124721670471

 PubMed Web of Science ®Google Scholar

MorganGJDaviesFEGregoryWMCyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantationBlood201111851231123821652683

 PubMed Web of Science ®Google Scholar

PalumboAHajekRDelforgeMContinuous lenalidomide treatment for newly diagnosed multiple myelomaN Engl J Med2012366191759176922571200

 PubMed Web of Science ®Google Scholar

BenboubkerLDimopoulosMADispenzieriALenalidomide and dexamethasone in transplant-ineligible patients with myelomaN Engl J Med20143711090691725184863

 PubMed Web of Science ®Google Scholar

MagarottoVBringhenSMustoPDoublet vs triplet lenalidomide-containing regimens in newly diagnosed myeloma patients, younger or older than 75 years: subgroup analysis of a phase III studyBlood2014124212110

 Web of Science ®Google Scholar

PalumboABringhenSLaroccaABortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survivalJ Clin Oncol201432763464024449241

 PubMed Web of Science ®Google Scholar

NiesvizkyRFlinnIWRifkinRCommunity-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimensJ Clin Oncol201533333921392926056177

 PubMed Web of Science ®Google Scholar